Emerging treatments in the management of psoriasis: biological targeting with ustekinumab

Psoriasis is a chronic, genetically determined, immune-mediated, inflammatory skin disease affecting approximately 2% to 3% of Caucasian population. Given the well-established role of the immuno-mediated inflammation in the pathogenesis of psoriasis, in the past few years several key steps in the pathogenesis of this disease have been elucidated and the increased knowledge led to the development of specific drugs, commonly defined as “biologics” targeting one or more of these steps. At present an anti-CD11a antibody (efalizumab), an anti-LFA3/CD2 receptor (alefacept) and 3 antitumor necrosis factor alpha agents (adalimumab, etanercept, infliximab) are now commercially available for the treatment of both psoriasis and psoriatic arthritis. Recent studies have demonstrated that interleukins (IL) 12 and 23 play an important role in the pathophysiology of psoriasis. In fact members of the IL-12 family of cytokines have the potential to act as the next major cytokine(s) in pathogenesis and the treatment of psoriasis. Ustekinumab (CNTO 1275, Centocor Inc, Malvern, PA, USA) is a human monoclonal antibody that binds to the shared p40 protein subunit of human interleukins 12 and 23 with high affinity and specificity, thereby preventing interaction with their surface IL-12Rβ1 receptor. Different clinical studies have been conducted to date. In particular a phase II study and two phase III studies, PHOENIX 1 together with PHOENIX 2, show very encouraging results. This review reports on the latest progress made in the clinical use of biologic drugs for psoriasis focusing on the new human IL-12/23 monoclonal antibody, ustekinumab, for psoriasis

Drug Survival of Interleukin (IL)‑17 and IL‑23 Inhibitors for the Treatment of Psoriasis: A Retrospective Multi‑country, Multicentric Cohort Study

Background: Drug survival, defined as the length of time from initiation to discontinuation of a given therapy, allows comparisons between drugs, helps to predict patient's likelihood of remaining on a specific treatment, and achieving the best decision for each patient in daily clinical practice. Objective: The aim of this study was to provide data on drug survival of secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab in a large international cohort, and to identify clinical predictors that might have an impact on the drug survival of these drugs. Methods: This was a retrospective, multicentric, multi-country study that provides data of adult patients with moderate to severe psoriasis who started treatment with an interleukin (IL)-17 or IL-23 inhibitor between 1 February 2015 and 31 October 2021. Data were collected from 19 distinct hospital and non-hospital-based dermatology centers from Canada, Czech Republic, Italy, Greece, Portugal, Spain, and Switzerland. Kaplan-Meier estimator and proportional hazard Cox regression models were used for drug survival analysis. Results: A total of 4866 treatment courses (4178 patients)-overall time of exposure of 9500 patient-years-were included in this study, with 3164 corresponding to an IL-17 inhibitor (secukinumab, ixekizumab, brodalumab) and 1702 corresponding to an IL-23 inhibitor (guselkumab, risankizumab, tildrakizumab). IL-23 inhibitors had the highest drug survival rates during the entire study period. After 24 months of treatment, the cumulative probabilities of drug survival were 0.92 (95% confidence interval [CI] 0.89-0.95) for risankizumab, 0.90 (95% CI 0.88-0.92) for guselkumab, 0.80 (95% CI 0.76-0.84) for brodalumab, 0.79 (95% CI 0.76-0.82) for ixekizumab, and 0.75 (95% CI 0.73-0.77) for secukinumab. At 36 months, only guselkumab [0.88 (95% CI 0.85-0.91)], ixekizumab [0.73 (95% CI 0.70-0.76)], and secukinumab [0.67 (95% CI 0.65-0.70)] had more than 40 patients at risk of drug discontinuation. Only two drugs had more than 40 patients at risk of drug discontinuation at 48 months, with ixekizumab demonstrating to have a higher cumulative probability of drug survival [0.71 (95% CI 0.68-0.75)] when compared with secukinumab [0.63 (95% CI 0.60-0.66)]. Secondary failure was the main cause for drug discontinuation. According to the final multivariable model, patients receiving risankizumab, guselkumab, and ixekizumab were significantly less likely to discontinue treatment than those receiving secukinumab. Previous exposure to biologic agents, absent family history of psoriasis, higher baseline body mass index (BMI), and higher baseline Psoriasis Area and Severity Index (PASI) were identified as predictors of drug discontinuation. Conclusion: The cumulative probability of drug survival of both IL-17 and IL-23 inhibitors was higher than 75% at 24 months, with risankizumab and guselkumab demonstrating to have overall cumulative probabilities ≥ 90%. Biological agent chosen, prior exposure to biologic agents, higher baseline BMI and PASI values, and absence of family history of psoriasis were identified as predictors for drug discontinuation. Risankizumab, guselkumab, and ixekizumab were less likely to be discontinued than secukinumab

The use of deacetylase inhibitors in dermatology

Η αναδιαμόρφωση της χρωματίνης καθώς επίσης και οι δυναμικέςαλλαγές που συντελούνται στο επίπεδο των πυρηνοσωμάτιων παίζουνπολύ σημαντικό ρόλο ως αναφορά τη ρύθμιση της γονιδιακής έκφρασηςεπηρεάζοντας έτσι τον κυτταρικό πολλαπλασιασμό, τη κυτταρικήδιαφοροποίηση και την απόπτωση. Ένας από τους ποιο σημαντικούςμηχανισμούς που εμπλέκονται στην αναδιαμόρφωση της χρωματίνης είναιοι μετά-μεταγράφηκες αλλαγές των ιστονών μέσω της ακετυλίωσης των Ν-τελικών οπίσθιων τμημάτων τους. Η ακετυλίωση αυτή επιτυγχάνεται με τημεσολάβηση ενζύμων που διαθέτουν ακετύλιο-τρανσφεράσηδραστηριότητα (ΗΑΤ), ενώ η αποακετυλίωση επιτυγχάνεται μέσωαποακετυλικών ενζύμων είτε της οικογενείας των ΗDΑC είτε της οικογενείαςτων Sir2. Η μεταβολή των μηχανισμών τόσο της ακετυλίωσης όσο και τηςαποακετυλίωσης συχνά εμπλέκονται στη παθογένεια των νεοπλασιών.Οι αναστολείς της αποακετυλίωσης των ιστόνων αποτελούν μια νέα ομάδααντί-νεοπλαστικών φαρμάκων ικανών να μεταβάλουν τη σχέση μεταξύακετυλίωσης και αποακετυλίωσης. Η μεταβολή αυτή με τη σειρά της μπορείνα οδηγήσει στην ισχυροποίηση της δράσης των νεοπλαστικώνφαρμάκων, οδηγώντας, προηγουμένως ανθεκτικά κύτταρα, στηναπόπτωση.Το βαλπροϊκό οξύ, είναι ένα φάρμακο που χρησιμοποιείται ευρέως για τηθεραπεία της επιληψίας επιδεικνύοντας μια έντονη ανασταλτική δράσηέναντι των αποακετυλικών ενζύμων της οικογενείας των ΗDΑC.Η ταζαροτένη, αποτελεί ένα μέλος της νέας οικογένειας των ακετυλενικώνρετινοιδών φαρμάκων, και έχει αποδειχθεί αποτελεσματική για τη θεραπείαδιάφορων υπερπλαστικών παθήσεων του δέρματος, όπως η ψωρίαση καιτων μη μελανωτικών νεοπλασμάτων του δέρματος. Η μοριακή της μορφήέχει σχεδιαστεί με τέτοιο τρόπο ώστε να είναι επιλεκτική ως προς τουςπυρηνικούς υποδοχείς RAR και πιο συγκεκριμένα RARβ και RARγ. Σκόπος της μελέτης αυτής είναι η κατανόηση των μηχανισμών τηςαντινεοπλασματικής δράσης του ακετυλενικού ρετινοϊδους, ταζαροτένηςκαι του αναστολέα της αποακετυλίωσης, βαλπροϊκου οξέος καθώς και ηδιερεύνηση της δυνατότητας ισχυροποίησης της αποτελεσματικότηταςτόσο της ταζαροτένης όσο και του ρετινοϊκου οξέος με τη ταυτόχρονηχορήγηση του βαλπροϊκου οξέος στην αντιμετώπιση μη μελανωτικώνκαρκίνων του δέρματος και συγκεκριμένα του βασικοκυτταρικούκαρκινώματος.Για το σκοπό αυτό αρχικά μελετήθηκε η διαφορική έκφραση τωνογκογονιδίων της οικογένειας p53 και πιο συγκεκριμένα των ισόφορμωνΤΑp73 και ΔΝ p73, του ογκογονιδίου p73 σε κυτταρικές καλλιέργειες C5Ν(Mouse immortalized keratinocytes cell line) και ΗaCaT (Humanimmortalized keratinocytes) κατόπιν ερεθισμού με ταζαροτένη). Οερεθισμός των παραπάνω κυτταρικών καλλιεργιών με ταζαροτένη οδήγησεστη μεταβολή της έκφρασης του ογκογονιδίου p73, προάγωντας την προ-αποπτωτική και αντι-αναπαραγωγική ισοφόρμα ΤΑp73, από τη μία, καικαταστέλωντας τη αντι-αποπτωτική και προ-αναπαραγωγική ισοφόρμα ΔΝp73, από την άλλη. Στη συνέχεια μέλετήθηκε η επίπτωση στο κυτταρικόκύκλο και στην απόπτωση της ταυτόχρονης χρήσης της ταζαροτένης καιτου βαλπροϊκού οξέος σε κυτταρικές καλλιέργειες κερατινικυττάρων ΗaCaT,δείχνοντας πώς η ταυτόχρονη χρήση των δύο αυτών παραγόντων ενισχύειτην αποπτωτική δράση της ταζαροτένης.Η ενίσχυση της αντινεοπλασματικής δράσης της ταζαροτένηςπαρατηρήθηκε και σε κλινικό επίπεδο με τη συγχορήγηση, τοπικά, γέληςταζαροτένης 0,1% και γέλης βαλπροϊκου οξέος 3% σε 8 ασθενείς μεβασικοκυτταρικά καρκινώματα

IKKα Is a p63 Transcriptional Target Involved in the Pathogenesis of Ectodermal Dysplasias

The transcription factor p63 plays a pivotal role in the development and differentiation of the epidermis and epithelial appendages. Indeed, mutations in p63 are associated with a group of ectodermal dysplasias characterized by skin, limb, and craniofacial defects. It was hypothesized that p63 exerts its functions by activating specific genes during epidermal development, which in turn regulate epidermal stratification and differentiation. We have identified I-kappaB kinase alpha (IKKα) as a direct transcriptional target of p63 that is induced at early phases of terminal differentiation of primary keratinocytes. We show that the ΔNp63 isoform is required for IKKα expression in differentiating keratinocytes and that mutant p63 proteins expressed in ectodermal dysplasia patients exhibit defects in inducing IKKα. Furthermore, we observed reduced IKKα expression in the epidermis of an ankyloblepharon ectodermal dysplasia clefting patient. Our data demonstrate that a failure to properly express IKKα may play a role in the development of ectodermal dysplasias

The Impact of Treatment with IL-17/IL-23 Inhibitors on Subclinical Atherosclerosis in Patients with Plaque Psoriasis and/or Psoriatic Arthritis: A Systematic Review

Accumulating evidence considers psoriasis a systemic inflammatory disorder that is associated with comorbidities such as psoriatic arthritis, cardiovascular disease, and metabolic syndrome. Although the precise pathogenetic links between psoriasis and atherosclerosis warrants further investigation, it is believed that chronic systemic inflammation along with the T helper (Th)-1 and Th17 polarization are associated with endothelial dysfunction and subsequent acceleration of atherosclerosis. Considering the above, several studies have evaluated if optimal control of the inflammation in psoriasis by inhibiting interleukins targeting the Interleukin (IL)-23/Th17 axis could subsequently reduce the atherosclerotic process during anti-psoriatic treatment by using a variety of surrogate markers of subclinical atherosclerosis. This systematic review summarizes current knowledge on the pathogenetic mechanisms and diagnostic evaluation of atherosclerosis in the context of psoriasis and provides a systematic review of the literature on the impact of treatment with biologics targeting the IL-23/Th17 axis on subclinical atherosclerosis in patients with plaque psoriasis and/or psoriatic arthritis

Treatment of Psoriasis Patients with Latent Tuberculosis Using IL-17 and IL-23 Inhibitors : A Retrospective, Multinational, Multicentre Study

Tuberculosis has a major global impact. Immunocompetent hosts usually control this disease, resulting in an asymptomatic latent tuberculosis infection (LTBI). Because TNF inhibitors increase the risk of tuberculosis reactivation, current guidelines recommend tuberculosis screening before starting any biologic drug, and chemoprophylaxis if LTBI is diagnosed. Available evidence from clinical trials and real-world studies suggests that IL-17 and IL-23 inhibitors do not increase the risk of tuberculosis reactivation. To evaluate psoriasis patients with treated or untreated newly diagnosed LTBI who received IL-17 and IL-23 inhibitors and the tolerability/safety of tuberculosis chemoprophylaxis. This is a retrospective, observational, multinational study from a series of 14 dermatology centres based in Portugal, Spain, Italy, Greece and Brazil, which included adult patients with moderate-to-severe chronic plaque psoriasis and newly diagnosed LTBI who were treated with IL-23 or IL-17 inhibitors between January 2015 and March 2022. LTBI was diagnosed in the case of tuberculin skin test and/or interferon gamma release assay positivity, according to local guideline, prior to initiating IL-23 or IL-17 inhibitor. Patients with prior diagnosis of LTBI (treated or untreated) or treated active infection were excluded. A total of 405 patients were included; complete/incomplete/no chemoprophylaxis was administered in 62.2, 10.1 and 27.7% of patients, respectively. The main reason for not receiving or interrupting chemoprophylaxis was perceived heightened risk of liver toxicity and hepatotoxicity, respectively. The mean duration of biological treatment was 32.87 ± 20.95 months, and only one case of active tuberculosis infection (ATBI) was observed, after 14 months of treatment with ixekizumab. The proportion of ATBI associated with ixekizumab was 1.64% [95% confidence interval (CI): 0-5.43%] and 0% for all other agents and 0.46% (95% CI 0-1.06%) and 0% for IL-17 and IL-23 inhibitors, respectively (not statistically significant). The risk of tuberculosis reactivation in patients with psoriasis and LTBI does not seem to increase with IL-17 or IL-23 inhibitors. IL-17 or IL-23 inhibitors should be preferred over TNF antagonists when concerns regarding tuberculosis reactivation exists. In patients with LTBI considered at high risk for developing complications related to chemoprophylaxis, this preventive strategy may be waived before initiating treatment with IL-17 inhibitors and especially IL-23 inhibitors